Pharmaceutical formulation

ABSTRACT

Pharmaceutical formulations comprising amoxycillin and clavulante in a ratio of from 10:1 to 20:1 are of use in the emperic treatment of infections potentially caused by DRSP.

This invention relates to pharmaceutical formulations comprising amoxycillin and a salt of clavulanic add (hereinafter termed “clavulanate” unless a specific salt is identified).

The combination of amoxycillin and clavulanate is an effective empirical treatment for bacterial infections and may be administered by oral dosing, for instance in the form of tablets, and, for paediatric formulations, aqueous solutions or suspensions, typically as a flavoured syrup.

Clavulante is a β-lactamase inhibitor and is included with the β-lactam antibiotic amoxycillin to counter a β-lactamase mediated resistance mechanism. Some microrganisms such as Streptococcus pneumoniae have resistance mechanisms which are not β-lactamase mediated. WO94/16696 discloses generally that potassium clavulanate may enhance the effectiveness of beta-lactam antibiotics such as amoxycillin against microorganisms having a resistance mechanism which is not β-lactamase mediated.

Streptococcus pneumoniae is an important pathogen in respiratory tract infection in the community. S. pneumoniae is the most commonly implicated bacterium in the important respiratory tract infections of otitis media in paediatrics and sinusitis in patients of all ages and acute exacerbations of bronchitis and pneumococcal pneumonia in adults. There have been increasing reports in Europe and the US of the emergence of DRSP (drug-resistant Streptococcus pneumoniae) with deceased suspectibility to β-lactam and other antibiotics.

Whilst confirmed cases of DRSP infection may be successfully treated with relatively high levels of amoxycillin, there still remains the need to develop effective empiric treatments, where DRSP may be suspected, for instance in an area with a high prevalence of DRSP, but where other, β-lactamase producing, organisms may also be present.

It has now been found that empiric treatment of infections potentially caused by DRSP may be successfully treated with formulations of co-amoxiclav which have a relatively large amount of amoxycillin.

Accordingly, the present invention provides a pharmaceutical formulation adapted for oral administration comprising amoxycillin and clavulanate in a weight ratio between 10:1 and 20:1 inclusive in combination with a pharmaceutically acceptable carrier or excipient.

Such formulations are of use for the empiric treatment of infections, potentially caused by DRSP, in particular respiratory tact infections such as otitis media in paediatrics and sinusitis in patients of all ages and acute exacerbations of bronchitis and pneumococcal pneumonia in adults.

The invention also provides for the use of amoxycillin and clavulanate in a ratio of between 10:1 and 20:1 inclusive in the manufacture of a medicament for oral administration for the empiric treatment of infections potentially caused by DRSP in human patients.

The invention also provides a method for the empiric treatment of infections potentially caused by DRSP in a human patient comprising the oral administration to a patient in need thereof of a pharmaceutical formulation comprising amoxycillin and clavulanate in a weight ratio between 10:1 and 20:1 inclusive.

The formulations of the present invention are suitable for use with patients of all ages, including adult, older children and and paediatric patients. The weight ratios of amoxycillin:clavulanate expressed herein are as free acid equivalent. Preferred amoxycillin:clavulanate ratios are between 12:1 to 16:1 inclusive, especially about 14:1±5%.

In the formulations of the invention the amoxycillin is preferably in the form of amoxycillin trihydrate, although sodium amoxycillin, for example the crystalline form of sodium amoxycillin which is disclosed in EP 0131147 A may also be used.

Clavulanate is preferably in the form of potassium clavulanate. Potassium clavulanate is extremely moisture-sensitive and should be stored and handled in conditions of 30% RH or less, ideally as low as possible Solid dosage forms should be packaged in atmospheric moisture-proof container and such forms and/or their containers may contain a desiccant.

The formulations of the invention may be made up into solid dosage forms for oral administration by a method conventional to the art of pharmaceutical technology, e.g. tablets or powder or granular products for reconstitution into a suspension or solution. Suitable ingredients and suitable methods for making such tablets are disclosed in for example GB 2 005 538-A. WO 92/19227 and WO 95/28927. Powder or granular formulations, such as paediatric suspension formulations, may be manufactured using techniques which are generally conventional in the field of manufacture of pharmaceutical formulations and in the manufacture of dry formulations for reconstitution into such suspensions. For example a suitable technique is that of mixing dry powdered or granulated ingredients for loading into a suitable container.

For paediatric dosing, the formulations of the invention are preferably made up into a sweet flavoured aqueous syrup formulation of generally conventional formulation (except for its novel amoxycillin:clavulanate ratio and intended use) containing a suitable weight of the amoxycillin and clavulanate in a unit dose volume. e.g. 5 ml or 2.5 ml of the syrup. Because of the water-sensitivity clavulanate it is preferred to provide such a syrup formulation as dry powder or granules contained in an atmospheric moisture-proof container or sachet for make up with water or other suitable aqueous medium shortly prior to use.

The formulation of this invention will normally, in addition to its active materials amoxycillin trihydrate and potassium clavulanate, also include excipients which are standard in the field of formulations for oral dosing and used in generally standard proportions, and at generally standard particle sizes and grades etc.

In the case of paediatric oral suspensions, these excipients may comprise suspending aids, glidants (to aid filling), diluents, bulking agent, flavours, sweeteners, stabilisers, and in the case of dry formulations for make up to an aqueous suspension, an edible desiccant to assist preservation of the potassium clavulanate against hydrolysis by atmospheric moisture on storage. Potassium clavulanate is normally supplied in admixture with silicon dioxide as diluent.

Suitable excipients for use include xantham gum (suspension aid), colloidal silica (glidant), succinic acid (stabiliser), aspartame (sweetener), hydroxypropyl-methylcellulose (suspension aid) and silicon dioxide (desiccant, diluent for potassium clavulanate and bulking agent). Flavours may comprise common flavours such as orange, banana, raspberry and golden syrup, or mixtures thereof, to suit local requirements.

Generally the proportion of active materials amoxycillin trihydrate and potassium clavulanate in a dry formulation for make up with aqueous media into a solution, suspension or syrup formulation of the invention may be around 30-80 wt %.

The present invention therefore also provides a process for manufacture of a formulation as described above.

The formulations of the invention may be adapted to paediatric dosing, i.e. to patients aged between 3 months to 12 years. Such formulations may be dosed in daily quantities up to the maximum normal permitted dose of amoxycillin and clavulanate.

A suitable dosage quantity of the formulation of the invention for paediatric patients is 75 to 115 mg/kg amoxycillin per day and 5 to 7.5 mg/kg of clavulanate per day. Suitably, the dosage is administered bid, for example in two, preferably equal, unit doses per day, suitably around 12 hours apart. A suitable dosage for use in such a regimen is 90±10%, especially ±5%, mg/kg amoxycillin and 6.4±10%, especially ±5%, mg/kg clavulanate (i.e. nominally a 14:1 ratio) per day.

Suitably, paediatric formulations as hereinbefore described are provided which comprise from 500 to 700, preferably about 600 mg of amoxycillin/5 ml of formulation when reconstituted and from 35 to 50 mg, preferably about 43 mg of clavulanic acid/5 ml of formulation when reconstituted.

For older children and adult patients these quantities may be increased pro rata. A suitable dosage for use in such a regimen is 3500±10%, especially ±5%, mg amoxycillin and 250±10%, especially ±5%, mg clavulanate (i.e. nominally a 14:1 ratio) per day, preferably administered bid, for example in two, preferably equal, unit doses per day, suitably around 12 hours apart.

The formulation of the invention may for example be provided in solid unit dose forms embodying suitable quantities for the administration of such a daily dose. For example a unit dosage form may be tablets, or sachets containing granules or powders for reconstruction, one or two of which are to be taken at each bid dosing interval. Alternatively a unit dose may be provided as a bulk of solid or solution or suspension, e.g. as a syrup for paediatric administration, together with a suitable measuring device of known type to facilitate administration of a suitable unit dose quantity of the formulation. A suitable unit dose quantity is one which enables the administration of the above-mentioned daily dosage quantity divided between two bid doses.

For paediatric patients, a suitable unit dose quantity is preferably one which enables the administration of the above-mentioned daily dosage quantity, divided between two bid doses, e.g. half of the above-mentioned daily dose, in a volume of a solution or suspension suitable for oral administration to a paediatric patient, preferably of between 2.5 to 10 ml, preferably as a syrup. A paediatric formulation may therefore comprise a bulk of a solution or suspension, e.g. a syrup, or granules or powder which can be made up into such a solution or suspension, at a concentration of solution or suspension which contains such a dose in such a volume.

The present invention therefore also provides the above described formulation provided for administration in such doses.

For adults, a suitable unit dose may be provided in a tablet. Suitably, for a bid dosage regimen based on 1750 mg amoxycillin/125 mg clavulanate per unit dose, this may conveniently be provided as two tablets, one comprising amoxycillin and clavulanate and a second comprising amoxycillin alone. Accordingly, in a further aspect, the present invention provides for a unit dosage of 1750 mg amoxycillin and 125 mg clavulante provided by two tablets, one comprising 875 mg amoxycillin and 125 mg clavulanate and a second comprising 875 mg amoxycillin. A suitable tablet comprising 875 mg amoxycillin and 125 mg clavulanate is marketed by SmithKline Beecham in several countries and is also described in WO 95/28927 (SmithKline Beeecham).

The invention will now be described by way of example only with reference to FIGS. 1, 2 and 3 which show graphically the results of Example 3 below.

FIGS. 1, 2 and 3 show respectively Log₁₀ of colony forming units (“cfu”) of S. Pneumoniae strains N1387, 14319 and 410101 per lungs observed in rats following dosing with an amoxycillin: potassium clavulanate (“AMX:CA”) formulation of this invention administered at 45:3.2 mg/kg amoxycillin:clavulanic acid equivalent, a comparison formulation administered at 22.5:3.2 mg/kg, and a non-treated control (“NTC”) as described below.

EXAMPLE 1 Paediatric Formulation

The following paediatric formulation comprising 600 mg amoxicillin and 42.9 mg clavulanic acid in 5 ml of suspension when reconstituted: Ingredient Quantity (mg) Amoxycillin trihydrate 697.00* (equivalent to amoxicillin free acid) 600.00 Potassium Clavulanate/Syloid 1:1 blend 113.00** (equivalent to clavulanic acid, including 8% overage) 46.332 Xanthan Gum 12.500 Aspartame 12.500 Succinic acid 0.835 Colloidal silicon dioxide 25.00 Hydroxypropyl methyl cellulose 79.650 Flavours 72.500 Silicon dioxide 86.315*** Total fill weight 1100.00 *based on 86% potency as amoxicillin free acid **based on 41% potency as clavulanic acid in potassium clavulante/Syloid 1:1 blend, including an 8% overage ***quantity of silicon dioxide (Syloid) varies, according to quantities of amoxycillin trihydrate and potassium clavulanate/Syloid blend, such that total fill weight remains constant at 1100.00 mg

Bottles are filled with 23.92 g of formulated powder and then reconstituted with 84 ml of water immediately prior to use, to give 100 ml of suspension.

EXAMPLE 2 Tablet Formulation

A tablet formulation comprising 875 mg amoxycillin and 125 mg clavulanate was prepared having the following composition: Ingredient (mg.) wt. % Active Constituents: Amoxycillin trihydrate 1017.4 70.2 (equivalent to amoxycillin) 875.00 Potassium clavulanate 152.45 10.5 (equivalent to clavulanic 125.0 acid) Other Constituents: Magnesium Stearate 14.50 1.00 Sodium Starch Glycollate 29.00 2.00 Colloidal Silicon Dioxide 10.0 0.70 Microcrystalline Cellulose 226.65 15.6 Core tablet weight 1450.00 100.00

The tablets are made by blending the amoxycillin, potassium clavulanate, and portions of microcrystalline cellulose and magnesium stearate, roller compacting this blend, then blending with the other constituents, before tabletting on a conventional tablet press and coating. The tablet core is coated with a film (Opadry White YS-1-7700/Opadry White OY-S-7300 ex Colorcon) from an aqueous solvent system, to give tablets with a nominal coated weight of 1482 mg. Further details of how the tablets are manufactured are provided in WO 95/28927 (SmithKline Beecham).

Similar tablets can be made in which the roller compaction step is replaced by slugging and/or a final film coating is applied from an organic solvent system such as dichloromethane rather than an aqueous solvent system.

A tablet formulation comprising 875 mg amoxycillin was prepared having the following composition: Core components (mg/tablet) Amoxicillin trihydrate 1017.4 (875 fa) Crospovidone. NF 30.5 Microcrystalline cellulose, NF 204.4 Sodium starch glycollate, NF 26.0 Colloidal Silicon Dioxide, NF 8.7 Magnaesium stearate, NF 13.0 Flim Coat Opadry Pink 39.0

The tablets are made by blending the amoxycillin and portions of microcrystalline cellulose and magnesium stearate, roller compacting this blend, then blending with the other constituents, before tableting on a conventional tablet press and coating.

EXAMPLE 3 Biological Data—In Vivo Rat Model

Methodology.

Animals were anaesthetised and the external jugular vein was cannulated for administration of compounds. At least 48 h later animals were infected by intra-bronchial instillation of a 50 microlitre inoculum of S. Pneumoniae by non surgical intubation. Inocula were prepared in cooled molten nutrient agar with a final inoculum of approximately 10⁶ cfu in 50 microlitres of agar. Dosing commenced 24 h after infection and compounds were administered as a continuous infusion into the jugular vein designed to simulate in rat plasma the concentration versus time curves obtained in human serum following oral administration of amoxycillin/clavulanate. For each organism tested, three groups of animals were used. The first two groups received amoxycillin and clavulanate to simulate bid dosing of this combination at either 22.5/3.2 mg/kg (a 7:1 ratio) or 45/3.2 mg/kg (a 14:1 ratio) to children. The remaining group received an infusion of saline at a rate similar to the dosed groups and acted as infected non-treated controls. Dosing continued for 2-5 days, and 14 days after therapy ended the animals were killed and lungs removed aseptically for bacteriological assessment.

Results

Table 1 shows the MIC's of amoxycillin, amoxycillin:clavulanate and penicillin G for the three resistant stains of S. Pneumoniae tested. TABLE 1 MIC(mcg/ml) Strain Amoxycillin Amox:clav. Penicillin G N1387 2 2 2 (R) 14319 4 4 8 (R) 410101 4 4 4 (R) Streptococcus Pneumoniae N1387:

Bacterial numbers in the lungs of saline-treated animals were 6.97±0.30 log₁₀ cfu/lungs. Both doses of amoxycillin:clavulanate reduced the numbers of viable bacteria in the lungs significantly compared with control animals (4.37±0.93 log₁₀ cfu/lungs and 2.62±0.85 log₁₀ cfu/lungs for the 7:1 and 14:1 ratios respectively, p<0.01). However as shown in FIG. 1 amoxycillin:clavulanate at the 14:1 bid ratio was significantly more effective than when administered at the lower ratio of 7:1.

Streptococcus Pneumoniae 14319:

Bacterial numbers in the lungs of sale-treated animals were 6.8±0.62 log₁₀ cfu/lungs. Amoxycillin:clavulanate at the 7:1 ratio reduced the numbers of viable bacteria in the lungs (6.26±0.47 log₁₀ cfu/lungs) but this reduction did not reach significance compared with control animals. However as shown in FIG. 2 amoxycillin:clavulanate at the 14:1 ratio bid reduced the bacterial count to 4.28±0.82 log₁₀ cfu/lungs such that this dose was significantly more effective than control animals and animals treated with the lower ratio of 7:1.

Streptococcus Pneumoniae 410101.

Bacterial numbers in the lungs of saline-treated animals were 7.11±0.45 log₁₀ cfu/lungs. Amoxycillin:clavulanate at the 7:1 ratio reduced the numbers of viable bacteria in the lungs (6.14±0.6 log₁₀ cfu/lungs) significantly compared with control animals (p. 0.05). However as shown in FIG. 3 amoxycillin:clavulanate at the 14:1 ratio bid reduced the counts to 3.91±0.81 log₁₀ cfu/lungs and was significantly more effective than animals treated with the lower ratio of 7:1. 

1-15. (canceled)
 16. A container comprising a powder or granular product for reconstitution into a suspension or solution upon the addition of water prior to use, said product comprising amoxycillin and clavulanate, wherein the concentration of the amoxycillin in the reconstituted suspension or solution is about 600 mg/5 ml and the ratio of amoxycillin to clavulanate is 14:1+/5%.
 17. The container as claimed in claim 16 wherein the amount of clavulanate is about 43 mg/5 ml.
 18. The container as claimed in claim 16 where upon the addition of water contains about 100 ml reconstituted suspension or solution.
 19. The container as claimed in claim 16 in which amoxycillin is in the form of amoxycillin trihydrate.
 20. The container as claimed in claim 16 in which amoxycillin is in the form of crystalline sodium amoxycillin.
 21. The container as claimed in claim 16 in which clavulanate is in the form of potassium clavulanate.
 22. The container as claimed in claim 16 which further comprises an edible desiccant.
 23. The container as claimed in claim 22 wherein the desiccant is silicon dioxide.
 24. The container as claimed in claim 16 which further comprises at least one of a diluent, a suspending agent, a glidant, a bulking agent, a flavour, a sweetener and a stabilizer.
 25. The container as claimed in claim 24 wherein the suspending agent is xanthan gum and hydroxypropylmethyl cellulose, or a mixture thereof; the glidant is colloidal silica; the stabilizer is succinic acid; the sweetener aspartame; and the bulking agent is silicon dioxide.
 26. The container as claimed in claim 24 wherein the flavour is selected from banana, raspberry, orange, golden syrup, or mixtures thereof.
 27. The container as claimed in claim 16 wherein the reconstituted solution is a flavoured aqueous syrup.
 28. The container as claimed in claim 16 which comprises the reconstituted suspension or solution.
 29. The container as claimed in claim 16 which is moisture proof.
 30. A container comprising a powder or granular product for reconstitution into a suspension or solution upon the addition of water prior to use, said product comprising amoxycillin and clavulanate, wherein the concentration of clavulanate when reconstituted is from about 35 to 50 mg/5 ml and the ratio of amoxycillin to clavulanate is 14:1+/5%.
 31. The container as claimed in claim 30 wherein the amount of clavulanate in the product is about 43 mg/5 ml.
 32. The container as claimed in claim 30 wherein the amount of amoxycillin in the product is from about 500 to 700 mg/5 ml.
 33. The container as claimed in claim 30 where upon the addition of water contains 100 ml reconstituted suspension or solution.
 34. The container as claimed in claim 30 in which the amoxycillin in the product is in the form of amoxycillin trihydrate.
 35. The container as claimed in claim 30 in which the amoxycillin in the product is in the form of crystalline sodium amoxycillin.
 36. The container as claimed in claim 30 in which the clavulanate in the product is in the form of potassium clavulanate.
 37. The container as claimed in claim 30 which product further comprises an edible desiccant.
 38. The container as claimed in claim 37 wherein the desiccant is silicon dioxide.
 39. The container as claimed in claim 301 which product further comprises at least one of a diluent, a suspending agent, a glidant, a bulking agent, a flavour, a sweetener and a stabilizer.
 40. The container as claimed in claim 39 wherein the suspending agent is xanthan gum and hydroxypropylmethyl cellulose, or a mixture thereof; the glidant is colloidal silica; the stabilizer is succinic acid; the sweetener aspartame; and the bulking agent is silicon dioxide.
 41. The container as claimed in claim 30 wherein the reconstituted solution is a flavoured aqueous syrup.
 42. The container as claimed in claim 39 wherein the flavour is selected from banana, raspberry, orange, golden syrup, or mixtures thereof.
 43. The container as claimed in claim 30 which is moisture proof. 